WO1998021207A1

WO1998021207A1 - (2,3-dihydrobenzofuranyl)-thiazoles as phosphodiesterase inhibitors

Info

Publication number: WO1998021207A1
Application number: PCT/EP1997/006131
Authority: WO
Inventors: Thomas Bär; Wolf-Rüdiger Ulrich; Hermann Amschler; Thomas Martin; Dieter Flockerzi; Beate Gutterer; Karl-Josef Goebel; Armin Hatzelmann; Hildegard Boss; Dietrich Häfner; Hans-Peter Kley; Rolf Beume
Original assignee: Byk Gulden Lomberg Chemische Fabrik Gmbh
Priority date: 1996-11-12
Filing date: 1997-11-05
Publication date: 1998-05-22
Also published as: EP0941226A1; JP2001504462A; AU5652698A; US6043263A

Abstract

The invention relates to compounds of the formula (I), wherein R1, R2, R3, R4, R5 and n have the meanings cited in the description, said compounds being new effective bronchial therapeutic agents. .

Description

(2,3-DIHYDROBENZOFURANYD THIAZOLE AS A PHOSPHODIESTERASE INHIBITOR

Field of application of the invention

The invention relates to new thiazole derivatives which are used in the pharmaceutical industry for the manufacture of medicaments.

Known technical background

Japanese patent JP 46-15935 describes substituted 4- (carboxyphenyl) thiazoles and their use for the treatment of thrombosis, arteriosclerosis, gastric ulcers and hypersecretion. European patent applications EP 0 513 387 and EP 0 600 092 describe, inter alia, 4- (substituted phenyl) thiazole derivatives, 4- (substituted 2,3-dihydrobenzofuran) thiazole derivatives and their use as inhibitors of oxygen radical release by neutrophils. The compounds are therefore described as being suitable for the treatment of acute inflammatory processes such as ischemia and reperfusion damage.

International patent application WO94 / 12461 describes 4-substituted catechol diethers which are substituted in the 4-position with, inter alia, thiazole derivatives and their use as inhibitors of phosphodiesterase IV.

Description of the invention

It has now surprisingly been found that the new thiazole derivatives described in more detail below, which differ from the previously published thiazoles in particular by the substituents on the 4- (2,3-dihydrobenzofuran ring), are selective inhibitors of phosphodiesterase IV.

The invention thus relates to compounds of the formula I (see attached formula sheet I), in which

R1 is hydroxy, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, benzyloxy or completely or predominantly fluorine-substituted 1-4C-alkoxy, R2 is hydrogen or 1-4C-alkyl and R3 is hydrogen or 1- 4C-alkyl means or R2 and R3 together and including the two carbon atoms to which they are attached represent a 5-, 6- or 7-membered hydrocarbon ring, optionally interrupted by an oxygen atom,

R4 represents a phenyl or naphthyl ring substituted by R41, R42 and R43, represents a mono- or bicyclic heterocycle substituted by R44, R45 and R46, which is selected from the group pyridine, pyrrole, quinoline, isoquinoline, indole, isoindole, indolizine, Pyrimidine, pyrazine, pyridazine, quinoxaline, quinazoline, cinnoline, benzimidazole, thiophene and furan or a mono- or bicyclic heterocycle substituted by R44 and R45, which is selected from the group pyrazole, imidazole, purine, oxazole, isoxazole, thiazole and isothiazole, wherein

R41 is hydrogen, carboxyl, 1-4C-alkoxycarbonyl, carbamoyl, hydroxysulfonyl, sulfamoyl, mono- or di-1-4C-alkylaminocarbonyl, mono- or di-1-4C-alkylaminosulfonyl, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkylsulfonyl, 1-4C-alkoxysulfonyl, hydroxy-1-4C-alkyl, hydroxy, 1-4C-alkoxy, 1-4C-alkyl, 1-4C-alkylcarbonyl, 1-4C-alkylcarbonyloxy, halogen, cyano or nitro,

R42 hydrogen, wholly or predominantly fluorine-substituted 1-4C-alkoxy, hydroxy, amino, nitro, halogen, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, 1-4C-alkyicarbonyl, carboxyl, 1-4C-alkyl or 1 -4C-alkoxy,

R43 is hydrogen, 1-4C-alkoxy, halogen or hydroxy,

R44 hydrogen, carboxyl, 1-4C-alkoxycarbonyl, carbamoyl, hydroxysulfonyl, sulfamoyl, mono- or di-1-4C-alkylaminocarbonyl, mono- or di-1-4C-alkylaminosulfonyl, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, hydroxy-1-4C-alkyl, hydroxy, 1-4C-alkoxy, 1-4C-alkyl, 1-4C-alkylcarbonyl, 1-4C-alkylcarbonyloxy, halogen, cyano or nitro,

R45 is hydrogen, hydroxy, halogen, carboxyl, amino, 1-4C-alkyl, 1-4C-alkylcarbonyl, 1-4C-alkoxycarbonyl or 1-4C-alkoxy and

R46 is hydrogen, halogen, 1-4C-alkoxy or 1-4C-alkyl,

R5 is hydrogen or halogen, n is 0, 1 or 2, the salts of these compounds and the N-oxides of pyridines, quinolines, isoquinolines, pyrimidines,

Pyrazines, imidazoles, quinoxalines, quinazolines and benzimidazoles and their salts.

1-4C-Alkyl stands for straight-chain or branched alkyl radicals with 1 to 4 carbon atoms. Examples include the butyl, iso-butyl, sec-butyl, tert-butyl, propyl, iso-propyl, ethyl and methyl radicals.

1-4C-alkoxy stands for a radical which, in addition to the oxygen atom, contains one of the above-mentioned straight-chain or branched alkyl radicals having 1 to 4 carbon atoms. As alkoxy residues with 1 up to 4 carbon atoms may be mentioned here, for example, butoxy, iso-butoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy, ethoxy and methoxy.

3-7C-Cycloalkoxy stands for the cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy radical. The 3-5C-cycloalkoxy radicals cyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.

3-7C-Cycloalkylmethoxy stands for Cyclopropylmethoxy, Cyclobutylmethoxy, Cyclopentylmethoxy, Cyclohexylmethoxy and Cycloheptylmethoxy. The 3-5C-cycloalkylmethoxy radicals cyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy may be mentioned as preferred.

Examples of 1 or 2,2-tri-fluoroethoxy, 2,2,3,3,3-pentafluoroethoxy, perfluoroethoxy and in particular 1, 1 2,2-tetrafluoroethoxy, the trifluoromethoxy, the 2,2,2-trifluoroethoxy and preferably the difluoromethoxy radical.

The cyclopentane, the cyclohexane, the cycloheptane, the tetrahydrofuran and the tetrahydropyran ring may be mentioned as a 5-, 6- or 7-membered hydrocarbon ring, optionally interrupted by an oxygen atom. If R2 and R3 together and including the two carbon atoms to which they are attached form a 5-, 6- or 7-membered ring, a spiro compound is present.

Halogen in the sense of the invention is fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine being preferred.

Examples of mono- or di-1-4C-alkylamino radicals are the methylamino, the dimethylamino, the ethylamino, the diethylamino, the propylamino and the isopropylamino radical.

Mono- or di-1-4C-alkylaminocarbonyl stands for a carbonyl group to which one of the abovementioned mono- or di-1-4C-alkylamino radicals is attached. The methylaminocarbonyl, dimethylaminocarbonyl and ethylaminocarbonyl radicals may be mentioned as examples.

Mono- or di-1-4C-alkylaminosulfonyl stands for a sulfonyl group to which one of the abovementioned mono- or di-1-4C-alkylamino residues is bonded. The methylaminosulfonyl, the dimethylaminosulfonyl and the ethylaminosulfonyl radical may be mentioned by way of example.

The 1-4C-alkylcarbonylamino radical may be mentioned, for example, the acetylamino radical (-NH-CO-CH ₃ ). 1-4C-alkoxycarbonyl stands for a carbonyl group to which one of the above-mentioned 1-4C-alkoxy radicals is attached. Examples include methoxycarbonyl (CH ₃ O-CO-) and ethoxycarbonyl (CH ₃ CH ₂ 0-CO-).

1-4C-alkylcarbonyl stands for a carbonyl group to which one of the above-mentioned 1-4C-alkyl radicals is attached. For example, the acetyl radical (CH ₃ CO-) may be mentioned.

In addition to the oxygen atom, 1-4C-alkylcarbonyloxy radicals contain a 1-4C-alkylcarbonyl radical. For example, the acetoxy residue (CH ₃ CO-O-) may be mentioned.

Hydroxy-1-4C-alkyl stands for the aforementioned 1-4C-alkyl radicals which are substituted by a hydroxyl group. For example, the hydroxyethyl and hydroxymethyl radicals may be mentioned.

1-4C-Alkylsulfonyl stands for a sulfonyl group to which one of the above-mentioned 1-4C-alkyl radicals is attached. For example, the methylsulfonyl radical (CH ₃ S0 ₂ -) may be mentioned.

1-4C-alkoxysulfonyl stands for a sulfonyl group to which one of the above-mentioned 1-4C-alkoxy radicals is attached. Examples include the methoxysulfonyl (CH ₃ 0-S0 ₂ -) and ethoxysulfonyl (CH ₃ CH ₂ 0-S0 ₂ -) groups.

The substituent R4 can be attached to the rest of the compounds of the formula I via any suitable ring position of the phenyl or naphthyl ring or of the heterocycle, the attachment of the heterocycles not taking place via a ring heteroatom.

Examples of R4 are phenyl, 3,4-dihydroxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3,5-dimethoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 3- Methoxy-4-hydroxyphenyl, 3-hydroxy-4-methoxyphenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-ethoxycarbonylphenyl, 3,4-diethoxyphenyl, 3,4-dimethylphenyl, 4-fluorophenyl, 3-chloro-4- methylphenyl, 3-nitrophenyl, 3,4-dichlorophenyl, 4-bromophenyl, 3,4-dibutoxyphenyl, 3,4-dipropoxyphenyl, 3-ethoxy-4-methoxyphenyl, 3-bromo-4,5-dimethoxyphenyl, 3,4-diacetoxyphenyl, 4-dimethylaminophenyl, 3-methoxy-4-methylsulfonylphenyl, 3-methoxycarbonyl-4-hydroxyphenyl, 4-acetamido-3-fluorophenyl, 4-acetamidophenyl, 4-acetamidonaphthyl, 4-acetamido 3-trifluoromethyoxyphenyl, 3-acetylphenyl, 4-acetylphenyl, 2-carbamoylphenyl, 3-carbamoylphenyl, 4-carbamoylphenyl, 2-carboxy-4-methoxyphenyl, 3-carboxyphenyl, 4-carboxyphenyl, 3-methoxycarbonylphenyl, 5-indol 4-nitrophenyl, 4-sulfonamidophenyl, 4-sulfophenyl, pyrimidin-2-yl, thioph en-3-yl, thiophene-2-yl, pyrrol-2-yl, 2-hydroxypyridin-3-yl, (pyridine-N-oxide) -3-yl, 5-acetyl-2-hydroxy-6-methylpyrid- 3-yl, 5-acetyl-2,4-dimethylpyrid-3-yl, 2-chloropyrid-3-yl, 2-chloropyrid-4-yl, 2-chloropyrazin-3-yl, quinolin-3-yl, 2,6-dihydroxy-4-methylpyrid-3-yl, 4-Ni tropyrid-2-yl, purin-6-yl, 2-carboxypyrid-4-yl, 2-ethoxycarbonylpyrid-4-yl, 6-methylpyrid-2-yl, pyrazine-2-yl, 2-pyridyl, 3- Called pyridyl and 4-pyridyl.

Suitable salts for compounds of the formula I - depending on the substitution - are all acid addition salts or all salts with bases. Particular mention should be made of the pharmacologically acceptable salts of the inorganic and organic acids and bases commonly used in galenics. Suitable as such are on the one hand water-soluble and water-insoluble acid addition salts with acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2- (4-hydroxybenzoyl) benzoic acid, butyric acid, sulfosalicylic acid, maleic acid , Lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, the acids in the salt production - depending on whether it is a mono- or poly-based acid and, depending on which salt is desired, be used in an equimolar or a different quantity ratio.

On the other hand, salts with bases can also be used. As examples of salts with bases, alkali (lithium, sodium, potassium) or calcium, aluminum, magnesium, titanium, ammonium, meglumine or guanidinium salts may be mentioned, the bases also being used here in salt production equimolar or a different ratio.

Pharmacologically incompatible salts, which may initially be obtained as process products in the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically acceptable salts by processes known to the person skilled in the art.

Compounds of formula I to be emphasized are those in which

R1 is 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy or completely or predominantly fluorine-substituted 1-4C-alkoxy,

R2 1-4C-aikyl and

R3 is hydrogen or 1-4C-alkyl, or

R2 and R3 together and including the two carbon atoms to which they are attached represent a cyclopentane, cyclohexane, tetrahydrofuran or tetrahydropyran ring,

R4 represents a phenyl ring substituted by R41 and R42 or represents a mono- or bicyclic heterocycle substituted by R44 and R45, which is selected from the group pyridine, pyrrole, quinoline, isoquinoline, indole, isoindole, indolizine, pyrimidine, pyrazine, pyridazine, pyrazole , Imidazole, quinoxaline, quinazoline, cinnoline, benzimidazole, oxazole, isoxazole, thiazole and isothiazole, where R41 is hydrogen, carboxyl, 1-4C-alkoxycarbonyl, carbamoyl, hydroxysulfonyl, sulfamoyl, mono- or di-1-4C-alkylaminocarbonyl, mono- or di-1-4C-alkylaminosulfonyl, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkylsulfonyl, 1-4C-alkoxysulfonyl, hydroxy-1-4C-alkyl, hydroxy, 1-4C-alkoxy, 1-4C-alkyl, 1-4C-alkylcarbonyl, 1-4C-alkylcarbonyloxy, halogen, cyano or nitro,

R42 is hydrogen, hydroxy, nitro, halogen, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, 1-4C-alkylcarbonyl, carboxyl or 1-4C-alkoxy,

R44 hydrogen, carboxyl, 1-4C-alkoxycarbonyl, carbamoyl, hydroxysulfonyl, sulfamoyl, mono- or di-1-4C-alkylaminocarbonyl, mono- or di-1-4C-alkylaminosulfonyl, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, hydroxy-1-4C-alkyl, hydroxy, 1-4C-alkoxy, 1-4C-alkyl, 1-4C-alkylcarbonyl, halogen or cyano and

R45 is hydrogen, hydroxy, halogen, carboxyl, amino, 1-4C-alkyl or 1-4C-alkoxy,

R5 is hydrogen or halogen, n is 0 or 1, the salts of these compounds and the N-oxides of pyridines, quinolines, isoquinolines, pyrimidines,

Imidazoles, quinoxalines, quinazolines and benzimidazoles and their salts.

Particularly noteworthy compounds of formula I are those in which

R1 is 1-4C-alkoxy, 3-5C-cycloalkoxy or completely or predominantly fluorine-substituted 1-2C-alkoxy,

R2 and R3 together and including the two carbon atoms to which they are attached represent a cyclopentane or cyclohexane ring,

R4 represents a phenyl ring substituted by R41 and R42 or represents a mono- or bicyclic heterocycle substituted by R44 and R45, which is selected from the group pyridine, pyrrole, quinoline, isoquinoline, indole, isoindole, indolizine and pyrazine, where

R45 is hydrogen, hydroxy, halogen, carboxyl, amino, 1-4C-alkyl or 1-4C-alkoxy,

R5 means hydrogen n 0 means the salts of these compounds and the N-oxides of pyridines, quinolines and isoquinolines and their

Salts.

Preferred compounds of formula I are those in which

R1 is 1-4C-alkoxy or completely or predominantly fluorine-substituted 1-2C-alkoxy,

R2 and R3 together and including the two carbon atoms to which they are attached form a cyclopentane ring,

R4 represents a phenyl ring substituted by R41 and R42 or represents pyridine or pyrazine substituted by R44 and R45, where

R45 is hydrogen, hydroxy, halogen, carboxyl, amino, 1-4C-alkyl or 1-4C-alkoxy,

R5 is hydrogen, n is 0, the salts of these compounds and the N-oxides of pyridines and their salts.

Particularly preferred compounds of the formula I are those in which

R1 is 1-4C-alkoxy,

R4 represents a phenyl ring substituted by R41 or represents pyridine substituted by R44, where

R41 is hydrogen, carboxyl, 1-4C-alkoxycarbonyl, carbamoyl, hydroxysulfonyl, sulfamoyl or hydroxy and

R44 is hydrogen, carboxyl, 1-4C-alkoxycarbonyl, carbamoyl, hydroxysulfonyl, sulfamoyl or hydroxy,

R5 means hydrogen, n means 0, as well as the salts of these compounds.

Particularly preferred compounds of formula I to be emphasized are those in which

R1 means methoxy

R41 carboxyl and

R44 is hydrogen, carboxyl or 1-4C-alkoxycarbonyl,

R5 is hydrogen, n is 0, and the salts of these compounds.

Exemplary compounds according to the invention are listed in the following tables:

Table 1

Compounds of the formula I with R4 = 3-pyridyl, 4-pyridyl, 3-carboxyphenyl, 6-carboxypyrid-4-yl or 6-ethoxycarbonylpyrid-4-yl, R5 = H, n = 0 and the following further substituent meanings:

Continuation of table 1

Table 2

Compounds of the formula I with R4 = 3-pyridyl, 4-pyridyl, 3-carboxyphenyl, 6-carboxypyrid-4-yl or 6-ethoxycarbonylpyrid-4-yl, R5 = H, n = 1 and the following further substituent meanings:

Continuation of table 2

If the substitutions -R2 and -CH ₂ R3 are not identical, the compounds of the formula I are chiral compounds. The invention therefore encompasses both the pure enantiomers and their mixtures in any mixing ratio, including the racemates. The enantiomers can be separated in a manner known per se (for example by preparing and separating corresponding diastereoisomeric compounds). Compounds of the formula I with identical substitutions -R2 and -CH ₂ R3 are preferred.

The invention further relates to a process for the preparation of the compounds of the formula I and their salts. The process is characterized in that compounds of the formula II (see attached formula sheet I) in which R1, R2, R3 and R5 have the meanings indicated above and Y is a suitable leaving group with compounds of the formula III (see attached formula sheet I) , in which R4 and n have the meanings given above and Z represents the group -C (S) -NH ₂ , and that, if desired, subsequently obtained compounds of the formula I in their salts or, if desired, subsequently obtained salts of the compounds of the Formula I converted into the free compounds.

The person skilled in the art is familiar with which leaving groups Y are suitable on the basis of his specialist knowledge. For example, suitable compounds of the formula II are assumed in which Y is halogen, in particular bromine or chlorine. Otherwise, the reaction is carried out in a manner familiar to the person skilled in the art (for example as described in EP 0 513 387 and EP 0 600 092) in a suitable solvent and in the presence or absence of a base, preferably at reaction temperatures between room temperature and the boiling point of the one used Lö- solvent and with reaction times between one hour and two days. Suitable solvents are, for example, alcohols such as methanol, ethanol or propanol, cyclic hydrocarbons such as toluene or xylene, ethers such as diethyl ether, tetrahydrofuran or dioxane, halogenated hydrocarbons such as dichloromethane or chloroform, polar solvents such as dimethylformamide, acetonitrile or dimethyl sulfoxide or, if desired, mixtures of the solvents mentioned. Preferred bases that are used are nitrogen bases such as triethylamine, ethyldiisopropylamine, N-methylmorpholine or pyridine. The bases can be added in an equimolar ratio (based on compounds of the formula III) or preferably in excess.

If desired, compounds of the formula I obtained can also be converted into other compounds of the formula I by using methods known to those skilled in the art. The preparation of carboxamides of the formula I from the corresponding carboxylic acids of the formula I may be mentioned as an example. For this purpose, the carboxylic acids of the formula I can be reacted with suitable amines in a manner known to those skilled in the art for the synthesis of carboxamides. If desired, the carboxylic acid of the formula I is converted into a suitably activated derivative, for example a corresponding acid halide, before the aminolysis. Examples of suitable amines which can be used are ammonia, methylamine or ethylamine.

The preparation of carboxylic acids of the formula I from corresponding esters of the formula I may also be mentioned by way of example, for example by hydrolysis in a manner known to the person skilled in the art, for example as described in the examples.

If desired, quinolines, isoquinolines, pyrimidines, pyrazines, imidazoles, quinoxalines, quinazolines, benzimidazoles and in particular pyridines of the formula I obtained can also be converted into the corresponding N-oxides or their salts.

The N-oxidation takes place in a manner also familiar to the person skilled in the art, e.g. with the help of m-chloroperoxibenzoic acid in dichloromethane at room temperature. The person skilled in the art is familiar with the reaction conditions which are required for carrying out the process in detail on the basis of his specialist knowledge.

The substances according to the invention are isolated and purified in a manner known per se, e.g. such that the solvent is distilled off in vacuo and the residue obtained is recrystallized from a suitable solvent or subjected to one of the customary purification methods, such as, for example, column chromatography on a suitable carrier material.

Salts are obtained by dissolving the free compound in a suitable solvent, for example in a chlorinated hydrocarbon such as methylene chloride or chloroform, or in a low molecular weight laren aliphatic alcohol (ethanol, isopropanol), which contains the desired acid or base, or to which the desired acid or base is then added. The salts are obtained by filtration, reprecipitation, precipitation with a non-solvent for the addition salt or by evaporation of the solvent. Salts obtained can be converted into the free compounds by alkalization or acidification, which in turn can be converted into salts. In this way, pharmacologically incompatible salts can be converted into pharmacologically acceptable salts.

The compounds of the formula II in which R1, R2, R3 and R5 have the meanings given above and Y is halogen, in particular chlorine or bromine, can be obtained in a known manner, for example by chlorination or bromination of corresponding compounds of the formula II in which Y is the meaning Has hydrogen.

The compounds of the formula II, in which R1, R2 and R3 have the meanings indicated above, R5 and Y represent hydrogen, can be obtained by reacting compounds of the formula IV (see attached formula sheet I) in which R1, R2 and R3 have the meanings indicated above have and A represents a nitrile group (-CN), with compounds of the formula CH ₃ -Mg-X, in which X is halogen, in particular chlorine or bromine, are prepared.

Compounds of the formula CH ₃ -Mg-X, in which X is halogen, in particular chlorine or bromine, are accessible from the corresponding compounds of the formula CH -X by reaction with magnesium in a manner familiar to the person skilled in the art.

Alternatively, compounds of the formula II in which R1, R2 and R3 have the meanings indicated above, R5 is hydrogen and Y halogen, in particular chlorine or bromine, by reacting compounds of the formula IV in which R1, R2 and R3 have the meanings indicated above and A represents an activated carboxylic acid derivative, for example a carboxylic acid halide, in particular carbonyl chloride [-C (0) CI] or carbonyl bromide [-C (0) Br], can be obtained with diazomethane and subsequent treatment with HCl or with HBr. The reactions are otherwise carried out in a manner known per se to the person skilled in the art.

The compounds of the formula III, in which R4 and n have the meanings given above and Z represents the group —C (S) —NH ₂ , are either known (for example from EP 0 513 387 or EP 0 600 092) or can be analogous or other ways known to the person skilled in the art, for example by adding hydrogen sulfide to corresponding compounds of the formula III in which Z is cyano (-CN) [W. Christ, D. Rakow, S. Strauss, J. Heterocycl. Chem. 11, 397 (1974)]. The corresponding compounds of the formula III, in which Z denotes cyano, can be described as described in the literature [for example analogously to T. Savaie, T. Ishiguro, K. Kawashima, K. Morita; Tetrahedron Lett. 1973, 2121-2124] from the corresponding compounds of formula III, in which Z is carbamoyl [-C (0) -NH ₂ ].

The compounds of the formula IV, in which R1, R2 and R3 have the meanings given above and A denotes a nitrile group, can be as described in the examples below or as described in the literature (T. Savaie, T.lshiguro, K. Kawashima, K. Morita; Tetrahedron Lett. 1973, 2121-2124) from the corresponding compounds of formula IV, in which A is carbamoyl [-C (0) -NH ₂ ].

The compounds of the formula IV in which A is carbamoyl can be prepared from the compounds of the formula IV in which A is carboxyl in a manner familiar to the person skilled in the art, for example as described in the examples below.

The compounds of the formula IV, in which R1, R2 and R3 have the meanings given above and A is a carboxylic acid halide, in particular carbonyl chloride [-C (0) CI], can be obtained from the compounds of the formula IV in which A has the meaning carboxyl , in a manner familiar to the person skilled in the art, for example as described in the examples below.

A further variant for the preparation of compounds of the formula II in which R1, R2, R3 and R5 have the meanings indicated above and Y represents hydrogen is the reaction of compounds of the formula IV in which R1, R2 and R3 have the meanings indicated above and A is lithium, with compounds of the formula R5-CH ₂ -C (0) W, where R5 has the meaning given above and W is a suitable leaving group. Particularly suitable leaving groups W are, for example, halogens, in particular chlorine or bromine or also 1-4C aikoxy radicals.

Compounds of the formula IV, in which R1, R2 and R3 have the meanings given above and A represents lithium, can be prepared from corresponding compounds of the formula IV, in which A represents halogen, in particular bromine, by reaction with an alkyl lithium compound, for example butyllithium, under receive usual reaction conditions.

Compounds of the formula IV, in which R1, R2 and R3 have the meanings given above and A has the meaning carboxyl, are either known from international patent application WO96 / 03399 or can be prepared in an analogous manner.

Compounds of the formula IV in which R1, R2 and R3 have the meanings indicated above and A is halogen, in particular bromine, can according to the general reaction scheme the attached formula sheet II are made from known precursors. The synthesis of corresponding compounds of the formula IV is described by way of example under starting compounds. Further compounds of formula IV can be prepared in an analogous manner.

Compounds of the formula R5-CH ₂ -C (0) W, in which R5 has the meaning given above and W represents a suitable leaving group, are either known or can be prepared in a manner known per se to the person skilled in the art from the corresponding compounds of the formula R5- CH ₂ -C (0) W, where W is hydroxy.

The following examples illustrate the invention without restricting it. Likewise, further compounds of the formula I, the preparation of which is not explicitly described, can be prepared in an analogous manner or in a manner familiar to the person skilled in the art using customary process techniques.

In the examples, mp stands for melting point, h for hour (s), RT for room temperature, min for minute (s), THF for tetrahydrofuran, DMF for dimethylformamide, Toi. for toluene, EA for ethyl acetate, TLC for thin layer chromatography and PE for petroleum ether. The compounds mentioned in the examples and their salts are a preferred subject of the invention.

Examples

End products

1. 3-r4- (2,3-Dihydro-7-methoxybenzofuran-2-spiro-1'-cvclopentan-4-yl) thiazol-2-vn-pyridine

488 mg (1, 5 mmol) 2-bromo-1- (2,3-dihydro-7-methoxybenzofuran-2-spiro-1'-cyclopentan-4-yl) -ethanone and 250 mg (1, 7 mmol) thionicotamic acid amide are stirred in 10 ml of ethanol at RT for 16 h. The suspension obtained is partitioned between 100 ml of ethyl acetate and 100 ml of 2N NaOH, the phases are separated and the organic phase is washed with 100 ml of saturated sodium chloride solution. The organic phase is dried over MgS0 ₄ , evaporated and the residue is recrystallized from 5 ml of 80% ethanol. 290 mg (53%) of the title compound of melting point 120-122 ° C. are obtained.

2. 4-r4- (2,3-Dihydro-7-methoxybenzofuran-2-spiro-1'-cvclopentan-4-yl) thiazol-2-vn-pyridine

439 mg (1, 35 mmol) 2-bromo-1- (2,3-dihydro-7-methoxybenzofuran-2-spiro-1'-cyclopentan-4-yl) -ethanone and 221 mg (1, 6 mmol ) Thioisonicotinic acid chloride are stirred in 10 ml of ethanol at RT for 20 h. The reaction mixture is partitioned between 50 ml of ethyl acetate and 50 ml of 2N NaOH, the phases are separated and the organic phase is washed with 50 ml of water and 50 ml of saturated sodium chloride solution. The organic phase is dried over MgS0 ₄ , evaporated and the resinous residue crystallized from 5 ml of ethanol. 172 mg (35%) of the title compound of mp 127-129 ° C. are obtained.

3. Ethyl 4-r4- (2,3-dihydro-7-methoxybenzofuran-2-spiro-1'-cvclopentan-4-yl) thiazol-2-vn-pyridine-2-carboxylate

488 mg (1, 5 mmol) 2-bromo-1- (2,3-dihydro-7-methoxybenzofuran-2-spiro-1'-cyclopentan-4-yl) -ethanone and 315 mg (1, 5 mmol) 4 -Thioamido-pyridine-2-carboxylic acid ethyl ester are reacted analogously to compound 2. After a reaction time of 24 h, 280 mg (41%) of the title compound of mp. 145-147 ° C. are obtained. 4. 4-r4- (2,3-Dihydro-7-methoxybenzofuran-2-spiro-1'-cvclopentan-4-yl) thiazol-2-vn-pyridine-2-carboxylic acid semihydrochloride

136 mg (0.3 mmol) of compound 3 and 28.7 mg (1.2 mmol) of lithium hydroxide are suspended in a mixture of 10 ml of methanol and 10 ml of water. After stirring at RT for 4 h, the now clear reaction solution is concentrated. The residue is dissolved in 5 ml of ethanol, acidified to pH = 0-1 with 6N HCl and the title compound is crystallized by adding 4 ml of water. It is filtered off, dried and 90 mg (69%) of the title compound of melting point 220 ° C. (decomposition) are obtained.

5. 3-r4- (2,3-Dihydro-7-methoxybenzofuran-2-spiro-1'-cyclopentan-4-yl) thiazol-2-vn-benzoic acid

975 mg (3.0 mmol) 2-bromo-1- (2,3-dihydro-7-methoxybenzofuran-2-spiro-1 '-cyclopentan-4-yl) -ethanone and 725 mg (4.0 mmol) 3 -Thioamidobenzoic acid are stirred for 3 days at RT with the addition of 1 ml of triethylamine in 20 ml of ethanol. The mixture is concentrated and the residue is taken up in 150 ml of ethyl acetate and 150 ml of water and acidified with 1N HCl until an acidic reaction occurs. The phases are separated, the aqueous phase is extracted twice with 50 ml of ethyl acetate each time and the combined organic phases are washed with 100 ml of saturated NaCl solution. The mixture is concentrated and chromatographed on silica gel (Tol / AcOH = 50: 1). The product-containing fractions are concentrated and the residue is crystallized from 50% ethanol. The title compound of mp. 215-217 ° C. is obtained.

Output connections

A. 2-Bromo-1- (2,3-dihydro-7-methoxybenzofuran-2-spiro-1'-cyclopentan-4-vπethanone

To a solution of 11.0 g (45 mmol) of 1- (2,3-dihydro-7-methoxybenzofuran-2-spiro-1'-cyclopentan- 4-yl) -ethanone in 160 ml of methanol, 2.8 is cooled with ice ml (54 mmol) of bromine was added dropwise. Then allowed to stir for 1 h. The reaction solution is mixed with 200 ml of ethyl acetate and extracted with 200 ml of water. The organic phase is separated off, washed first with saturated bicarbonate solution, then with saturated NaCl solution, dried over magnesium sulfate and concentrated. The resinous residue is chromatographed on silica gel (Tol / EA = 20: 1), the product-containing fractions are concentrated and recrystallized from 80 ml of petroleum ether. 6.4 g (44%) of the title compound of mp 73 ° -75 ° C. are obtained.

B. 1- (2,3-Dihvdro-7-methoxybenzofuran-2-spiro-1'-cyclopentan-4-yl) ethanone

To a solution of 10.7 g (47.0 mmol) of 4-cyano-2,3-dihydro-7-methoxybenzofuran-2-spiro-1 '-cyclopentane in 100 ml of THF, add 25 ml (75 mmol) at RT 20% solution of methyl magnesium chloride in THF. The mixture is then heated to reflux for 7 h. Then it is carefully hydrolyzed with 20 ml of water, mixed with 50 ml of semi-concentrated sulfuric acid and heated to reflux for 90 minutes. The phases are separated, the aqueous phase is extracted with 2 × 70 ml of ethyl acetate, and the combined organic phases are washed again with 100 ml of water, 100 ml of saturated sodium bicarbonate solution and 100 ml of saturated NaCl solution. It is dried over magnesium sulfate, concentrated and 11.0 g (96%) of the title compound are obtained, which is used for the synthesis of compound A without further purification.

C. 4-Cvano-2,3-dihydro-7-methoxybenzofuran-2-spiro-1 'cyclopentane

1.4 g (6.0 mmol) of 2,3-dihydro-7-methoxybenzofuran-2-spiro-1'-cyclopentane-carboxamide are dissolved in 25 ml of CHCI ₃ and mixed with 210 mg (1.0 mmol) of benzyltriethylammonium chloride. 5 ml of 50% NaOH are added with ice cooling and the mixture is stirred at 15 ° C. for 3 h. H ₂ 0 is added, the mixture is extracted with ethyl acetate and chromatographed on silica gel (Toi.). Crystallization takes place from 5 ml of petroleum ether and 998 mg (77%) of the title compound of mp 74-76 ° C. are obtained.

D. 2,3-Dihvdro-7-methoxybenzofuran-3-spiro-1'-cyclopentan-4-yl-carboxamide

3.5 g (14.0 mmol) of 2,3-dihydro-7-methoxybenzofuran-2-spiro-1 '-cyclopentan-4-yl-carboxylic acid are treated with 10 ml (approx. 140 mmol) of SOCI ₂ . The excess SOCI ₂ is distilled off in vacuo and the residue taken up in 20 ml of acetone. 10 ml of conc. NH ₃ and allowed to stir for 1 h. The acetone is distilled off and the residue is partitioned between ethyl acetate and 0.5 N NaOH. The dried organic phase is crystallized from 5 ml of 50% methanol and 115 mg (48%) of the title compound of mp 149-151 ° C. are obtained.

E. 2,3-Dihvdro-7-methoxybenzofuran-2-spiro-r-cyclopentan-4-yl-carboxylic acid

The representation of the title compound is described in international patent application WO96 / 03399.

F. 1- (2,3-Dihvdro-7-methoxybenzofuran-2-spiro-1'-cyclopentan-4-yl) ethanone

To a solution of 6.36 g (22.5 mmol) of 4-bromo-2,3-dihydro-7-methoxy-benzofuran-2-spiro-1 '-cyclopentane in 125 ml of diethyl ether, 17 ml are added at -50 ° C (27 mmol) of a 1, 6 N solution of butyllithium in heptane. The mixture is then stirred at 0 ° C. for 30 minutes, 10 ml of ethyl acetate are added at -60 ° C. and the reaction mixture is allowed to come to RT. The mixture is hydrolyzed at -20 ° C., then the aqueous phase is extracted with 50 ml of ethyl acetate, the combined organic phases are dried over magnesium sulfate and concentrated and chromatographed on silica gel (Tol / EA = 50: 1). The product-containing fractions are evaporated and the title compound is obtained as a colorless oil.

G. 4-Bromo-2,3-dihydro-7-methoxybenzofuran-2-spiro-1'-cvclopentane

9.0 g of Amberlist 15 are added to a solution of 8.4 g (0.03 mol) of the H. prepared compound in 100 ml of absolute toluene, and the mixture is stirred at 100 ° C. for 10 h. After the mixture has cooled, the H + ion exchanger is filtered off and washed with 100 ml of methanol. After stripping off the organic phase and column chromatography, 7.4 g (88% of theory) of the title compound are obtained as a yellow oil. [TLC (PE / ethyl ether, 6: 4) Rf = 0.72].

H. 4-Cvclopent-1-enylmethyl-3-hydroxy-4-methoxybromobenzene

52.1 ml (0.082 mol) of n-butyllithium are added dropwise to a suspension of 26.5 g (0.074 mol) of methyltriphenylphosphonium bromide in 200 ml of absolute THF at -78 ° C. under nitrogen. The suspension is then heated to -30 ° C, the suspension going into solution. After cooling again to -70 ° C., a solution of 19.2 g (0.067 mol) of the compound prepared according to I in 200 ml of absolute THF is added dropwise under nitrogen. The mixture is then warmed to -10 ° C. and stirred at this temperature for 5 h. [TLC (PE / ethyl ether, 6: 4) Rf (methylene compound) = 0.81]. After warming to RT, the mixture of solids is filtered off, the filtrate is shaken with 3x200 ml of semi-saturated sodium chloride solution and 2x200 ml of distilled water. After unification of the organic Phases, drying over sodium sulfate and concentrating to dryness, the residue is taken up in 50 ml of quinoline and stirred at 195-205 ° C for 1 h. After the solution has cooled, 400 ml of ethyl ether are added and the quinoline is shaken out with 4x200 ml of 2N hydrochloric acid. The organic phases are combined, dried over sodium sulfate and concentrated. Column chromatography gives a yield of 8.4 g (44% of theory) of the title compound as a red-brown oil. [TLC (PE / ethyl ether, 6: 4) Rf = 0.65].

I. Methoxy-3- (2-oxocclopentyloxy) bromobenzene

17.7 g (0.15 mol) of 2-chlorocyclopentanone and 41.4 g (0.3 mol) are added to a solution of 20 g (0.1 mol) of 3-hydroxy-4-methoxybromobenzene in 300 ml of absolute DMF. Potassium carbonate and stirred at RT for 12 h. After filtering off the solids, the filtrate is concentrated, taken up in 500 ethyl ether and shaken with 3x200 ml of distilled water. Column chromatography gives 21.1 g (75% of theory) of the title compound as a brown oil [TLC (PE / ethyl ether, 6: 4) Rf = 0.47].

J. 4-Cyanopyridine-2-carboxylic acid ethyl ester

A solution of 1.88 g (10.6 mmol) of 4-cyanopyridine-2-carboxylic acid ethyl ester in 10 ml of pyridine and 2 ml of triethylamine is saturated with hydrogen sulfide. After 16 h at RT, the mixture is concentrated, taken up in 100 ml of ethyl acetate and washed first with 100 ml of saturated sodium bicarbonate solution, then with 100 ml of water. The organic phase is dried over magnesium sulfate, concentrated and the residue is recrystallized from 20 ml of ethanol. 1.92 g (86%) of the title compound of mp 170 ° -172 ° C. are obtained.

K. 4-Cyanopyridine-2-carboxylic acid ethyl ester

The representation of the connection is known from the literature. Lit .: G. Heinisch, G. Lötsch; Appl. Chem. 97, 694 (1985).

L. 3-thiocarbamoyl-benzoic acid

The representation of the connection is known from the literature. Lit .: Science Union, German Patent 21 29 090 (1971); CA 76, 85810 (1972). Industrial applicability

The compounds according to the invention have valuable pharmacological properties which make them commercially usable. As selective cyclic nucleotide phosphodiesterase (PDE) inhibitors (of type IV), they are suitable on the one hand as bronchial therapeutics (for the treatment of airway obstructions due to their dilating but also due to their respiratory rate or respiratory drive increasing effect) and for the eradication of erectile dysfunction due to the vasodilating effect, on the other hand, however, primarily for the treatment of diseases, in particular inflammatory in nature, for example the respiratory tract (asthma prophylaxis), the skin, the intestine, the eyes and the joints, which are mediated by mediators such as histamine, PAF (platelet activating factor), arachidonic acid derivatives such as leukotrienes and prostaglandins, cytokines, interleukins, chemokines , alpha, beta and gamma interferon, tumor necrosis factor (TNF) or oxygen radicals and proteases. The compounds according to the invention are notable for low toxicity, good enteral absorption (high bioavailability), a wide therapeutic range and the absence of significant side effects.

On account of their PDE-inhibiting properties, the compounds according to the invention can be used as therapeutic agents in human and veterinary medicine, for example they can be used for the treatment and prophylaxis of the following diseases: Acute and chronic (in particular inflammatory and allergen-induced) respiratory diseases of various origins (bronchitis, allergic Bronchitis, bronchial asthma); Dermatoses (especially proliferative, inflammatory and allergic) such as psoriasis (vulgaris), toxic and allergic contact dermatitis, atopic eczema, seborrheic eczema, lying simplex, sunburn, pruritus in the genital area, alopecia areata, hypertrophic scars, discoid lupus follicular and extensive pyoderma, endogenous and exogenous acne, acne rosacea and other proliferative, inflammatory and allergic skin diseases; Diseases that are based on an excessive release of TNF and leukotrienes, such as diseases from the type of arthritis (rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and other arthritic conditions), diseases of the immune system (AIDS, multiple sclerosis), manifestations of shock [septic Shock, endotoxin shock, gram-negative sepsis, toxic shock syndrome and ARDS (adult respiratory distress syndrome)] as well as generalized inflammation in the gastrointestinal area (Crohn's disease and ulcerative colitis); Diseases based on allergic and / or chronic, immunological incorrect reactions in the area of the upper respiratory tract (pharynx, nose) and the adjacent regions (paranasal sinuses, eyes), such as allergic rhinitis / sinusitis, chronic rhinitis / sinusitis, allergic conjunctivitis and Nasal polyps; but also diseases of the heart that can be treated by PDE inhibitors, such as, for example, heart failure, or diseases that can be treated due to the tissue-relaxing effect of the PDE inhibitors, such as, for example, erectile dysfunction or colic of the kidneys. ren and the ureter related to kidney stones; or also diseases of the CNS, such as depression or arteriosclerotic dementia.

Another object of the invention is a method for the treatment of mammals, including humans, who are suffering from one of the abovementioned diseases. The method is characterized in that the sick mammal is administered a therapeutically effective and pharmacologically acceptable amount of one or more of the compounds according to the invention.

The invention further relates to the compounds according to the invention for use in the treatment and / or prophylaxis of the diseases mentioned.

The invention also relates to the use of the compounds according to the invention for the production of medicaments which are used for the treatment and / or prophylaxis of the diseases mentioned.

The invention furthermore relates to medicaments for the treatment and / or prophylaxis of the diseases mentioned, which contain one or more of the compounds according to the invention.

The pharmaceuticals are produced by methods known per se and familiar to the person skilled in the art. The compounds according to the invention (= active ingredients) are used as pharmaceuticals either as such or preferably in combination with suitable pharmaceutical auxiliaries, e.g. in the form of tablets, dragees, capsules, suppositories, plasters, emulsions, suspensions, gels or solutions, the active ingredient content advantageously being between 0.1 and 95%.

The person skilled in the art is familiar with the auxiliaries which are suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge. In addition to solvents, gel formers, ointment bases and other active substance carriers, for example antioxidants, dispersants, emulsifiers, preservatives, solubilizers or permeation promoters can be used.

For the treatment of diseases of the respiratory tract, the compounds according to the invention are preferably also administered by inhalation. For this purpose, these are administered either directly as a powder (preferably in micronized form) or by atomizing solutions or suspensions containing them. With regard to the preparations and dosage forms, reference is made, for example, to the explanations in European patent 163 965.

For the treatment of dermatoses, the compounds according to the invention are used in particular in the form of those medicaments which are suitable for topical application. The compounds according to the invention (= active substances) are preferred wisely mixed with suitable pharmaceutical excipients and processed into suitable pharmaceutical formulations. Suitable pharmaceutical formulations include, for example, powders, emulsions, suspensions, sprays, oils, ointments, fatty ointments, creams, pastes, gels or solutions.

The pharmaceuticals according to the invention are produced by methods known per se. The active ingredients are dosed in the order of magnitude customary for PDE inhibitors. For example, topical forms of application (such as ointments) for the treatment of dermatoses contain the active ingredients in a concentration of, for example, 0.1-99%. The dose for inhalation is usually between 0.01 and 1 mg per spray. The usual dose for systemic therapy po or iv is between 0.1 and 200 mg per application.

Biological studies

Activation of inflammatory cells is of particular importance when studying PDE IV inhibition at the cellular level. An example is the FMLP (N-formyl-methionyl-leucyl-phenylalanine) -induced superoxide production of neutrophil granulocytes, which can be measured as luminol-enhanced chemiluminescence. [Mc Phail LC, Strum SL, Leone PA and Sozzani S, The neutrophil respiratory burst mechanism. In "Immunology Series" 57: 47-76, 1992; ed. Coffey RG (Marcel Decker, Inc., New York-Basel-Hong Kong)].

Substances which inhibit chemiluminescence and the cytokine secretion and the secretion of inflammation-increasing mediators on inflammatory cells, in particular neutrophilic and eosinophilic granulocytes, are those which inhibit PDE IV. This isoenzyme of the phosphodiesterase families is particularly represented in granulocytes. Its inhibition leads to an increase in the intracellular cyclic AMP concentration and thus to the inhibition of cellular activation. The PDE IV inhibition by the substances according to the invention is thus a central indicator for the suppression of inflammatory processes. (Giembycz MA, Could isoenzyme-selective phosphodiesterase inhibitors render bronchodilatory therapy redundant in the treatment of bronchial asthma?. Biochem Pharmacol 43: 2041-2051, 1992; Torphy TJ et al., Phosphodiesterase inhibitors: new oppor- tunities for treatment of asthma. Thorax 46: 512-523, 1991; Schudt C et al., Zardaverine: a cyclic AMP PDE Ill / IV inhibitor. In "New Drugs for Asthma Therapy", 379-402, Birkhäuser Verlag Basel 1991; Schudt C et al., Influence of selective phosphodiesterase inhibitors on human neutrophil functions and levels of cAMP and Ca _j . Naunyn-Schmiedebergs Arch Pharmacol 344: 682-690, 1991; Nielson CP et al., Effects of selective phosphodiesterase inhibitors on polymorphonuclear leukocyte respiratory burst. J Allergy Clin Immunol 86: 801-808, 1990; Schade et al., The specific type III and IV phosphodiesterase inhibitor zardaverine suppress formation of tumor necrosis factor by macrophages. European Journal of Pharmacology 230: 9-14, 1993).

Inhibition of PDE IV activity

methodology

The activity test was carried out according to the Bauer and Schwabe method, which was adapted to microtiter plates (Naunyn-Schmiedeberg's Arch. Pharmacol. 311, 193-198, 1980). The PDE reaction takes place in the first step. In a second step, the resulting 5'-nucleotide is cleaved by a 5'-nucleotidase of the snake venom from ophiophagus hannah (King Cobra) to the uncharged nucleoside. In the third step, the nucleoside is separated from the remaining charged substrate on ion exchange columns. The columns are eluted with 2 ml of 30 mM ammonium formate (pH 6.0) directly in minivials, into which 2 ml of scintillator liquid is added for counting.

The inhibition values determined for the compounds according to the invention are shown in Table 1 below, in which the numbers of the compounds correspond to the numbers of the examples.

Table 1

Inhibition of PDE IV activity

Claims

claims

Compounds of the formula

in which R1 is hydroxy, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, benzyloxy or completely or predominantly fluorine-substituted 1-4C-alkoxy,

R2 is hydrogen or 1-4C-alkyl and R3 is hydrogen or 1-4C-alkyl, or

R2 and R3 together and including the two carbon atoms to which they are attached represent a 5-, 6- or 7-membered hydrocarbon ring, optionally interrupted by an oxygen atom,

R41 is hydrogen, carboxyl, 1-4C-alkoxycarbonyl, carbamoyl, hydroxysulfonyl, sulfamoyl, mono- or di-1-4C-alkylaminocarbonyl, mono- or di-1-4C-alkylaminosulfonyl, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkylsulfonyl, 1-4C-alkoxysulfonyl, hydroxy-1-4C-alkyl, hydroxy, 1-4C-alkoxy, 1-4C-alkyl, 1-4C-alkylcarbonyI, 1- 4C-alkylcarbonyloxy, halogen, cyano or nitro, R42 is hydrogen, wholly or predominantly fluorine-substituted 1-4C-alkoxy, hydroxy, amino, nitro, halogen, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, 1-4C-alkylcarbonyl, carboxyl, 1-4C-alkyl or 1 -4C-alkoxy,

R43 is hydrogen, 1-4C-alkoxy, halogen or hydroxy,

R46 is hydrogen, halogen, 1-4C-alkoxy or 1-4C-alkyl,

2. Compounds of formula I according to claim 1, in which

R2 1-4C alkyl and

R3 is hydrogen or 1-4C-alkyl, or

R4 represents a phenyl ring substituted by R41 and R42 or represents a mono- or bicyclic heterocycle substituted by R44 and R45, which is selected from the group pyridine, pyrrole, quinoline, isoquinoline, indole, isoindole, indolizine, pyrimidine, pyrazine, pyridazine, pyrazole , Imidazole, quinoxaline, quinazoline, cinnoline, benzimidazole, oxazole, isoxazole, thiazole and isothiazole, where

R41 is hydrogen, carboxyl, 1-4C-alkoxycarbonyl, carbamoyl, hydroxysulfonyl, sulfamoyl, mono- or di-1-4C-alkylaminocarbonyl, mono- or di-1-4C-alkylaminosulfonyl, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkylsulfonyl, 1-4C-alkoxysulfonyl, hydroxy-1-4C-alkyl, hydroxy, 1-4C-alkoxy, 1-4C-alkyl, 1-4C-alkylcarbonyl, 1- 4C-alkylcarbonyloxy, halogen, cyano or nitro,

R44 is hydrogen, carboxyl, 1-4C-alkoxycarbonyl, carbamoyl, hydroxysulfonyl, sulfamoyl, mono- or di-1-4C-alkylaminocarbonyl, mono- or di-1-4C-alkylaminosulfonyI, amino, mono- or Di-1-4C-alkylamino, 1-4C-alkylcarbonyiamino, hydroxy-1-4C-alkyl, hydroxy, 1-4C-alkoxy,

1-4C-alkyl, 1-4C-alkylcarbonyl, halogen or cyano and R45 are hydrogen, hydroxy, halogen, carboxyl, amino, 1-4C-alkyl or 1-4C-alkoxy, R5 is hydrogen or halogen, n is 0 or 1 means the salts of these compounds and the N-oxides of pyridines, quinolines, isoquinolines, pyrimidines, imidazoles, quinoxalines, quinazoines and benzimidazoles and their salts.

3. Compounds of formula I according to claim 1, in which

R45 is hydrogen, hydroxy, halogen, carboxyl, amino, 1-4C-alkyl or 1-4C-alkoxy,

R5 is hydrogen, n is 0, the salts of these compounds and the N-oxides of pyridines, quinolines and isoquinolines and their

Salts.

4. Compounds of formula I according to claim 1, in which

R1 is 1-4C-alkoxy or completely or predominantly substituted by fluorine-1-2C-alkoxy, R2 and R3 together and including the two carbon atoms to which they are attached represent a cyclopentane ring, R4 represents a phenyl ring substituted by R41 and R42 or represents pyridine or pyrazine substituted by R44 and R45, where

R45 is hydrogen, hydroxy, halogen, carboxyl, amino, 1-4C-alkyl or 1-4C-alkoxy,

R5 is hydrogen, n is 0, ^'the salts of these compounds and the N-oxides of the pyridines and their salts.

5. Compounds of formula I according to claim 1, in which R1 is 1-4C-alkoxy,

R5 is hydrogen, n is 0, and the salts of these compounds.

6. Compounds of formula I according to claim 1, in which R1 is methoxy,

R4 represents a phenyl ring substituted by R41 or represents pyridine substituted by R44, where R41 carboxyl and

R44 is hydrogen, carboxyl or 1-4C-alkoxycarbonyl,

R5 is hydrogen, n is 0, and the salts of these compounds.

7. Medicament containing one or more compounds according to claim 1, together with conventional pharmaceutical auxiliaries and / or carriers.

8. Compounds according to claim 1 for use in the treatment of diseases.

9. Use of compounds according to claim 1 for the manufacture of medicaments for the treatment of respiratory diseases.